Organic aminophosphonic acids and their salts are well known as is their use in chelating metal ions, some of which are used as threshold inhibitors. U.S. Pat. No. 2,599,807 is an early patent which discloses these and describes methods for their preparation. An example of the preparation in this patent discloses heating an aqueous solution of ethylenediamine and adding to this a solution of the sodium salt of chloromethylenephosphonic acid and an excess of a base, e.g. Na.sub.2 CO.sub.3 to maintain a pH of 10 to 11.5. After adding at least a stoichiometric amount of the phosphonating reagent, i.e. sufficient to form the completely phosphonated amine salt [sodium salt of ethylenediaminetetra(methylenephosphonic acid)], the solution is refluxed at its boiling point for from one to five hours. It is then cooled and neutralized to a pH of 6 to 7 and evaporated to dryness to recover the desired ethylenediaminetetra(methylenephosphonic acid).
Another method which makes the symmetrical ethylenediaminedi(methylenephosphonic acid) in good yield involves treating an aqueous solution of two molar portions of aminomethylenephosphonic acid with one molar portion of an alkylene dihalide at an elevated temperature for a time sufficient to insure complete reaction. This can be accomplished in a few hours under reflux in 50% ethanol.
In another patent, U.S. Pat. No. 3,738,987, the reaction to form the aminophosphonic acid is begun by introducing PCl.sub.3 into water to form phosphorous acid and HCl. The polyamine is then introduced into this solution. It is preferred to have a 5 to 10% excess of the PCl.sub.3. When the amine is added, the reaction medium is at a temperature of about 38.degree. to 50.degree. C. When all the amine has been added, the temperature is raised to 93.degree. to 104.degree. C. and an aqueous solution of formaldehyde is sparged into the reaction mixture, during which time the temperature is maintained at that level and for several hours thereafter and finally cooled.
In a more recent patent, Jap. No. 55-150501, it is disclosed that much higher yields are obtained by adding the amine to a mixture of phosphorous and hydrochloric acids in which the H.sub.3 PO.sub.3 is in excess with respect to the amine, preferably about 4.3 to 5.5 moles of the acid per mole of amine. Concentrated HCl is used, preferably about 2.2 moles HCl per mole of amine. Too much acid will tend to increase the amount of water in the system which is undesirable. No additional water is added to the reaction mixture, which is apparently the reason for the improved yields since all the other methods use water and dilute acids.
It has recently been discovered that certain of the methylenephosphonated amines are useful for imaging and other radiopharmaceutical uses when complexed as chelates with radioactive metals. Use for such purposes requires the highest purity materials.
The present inventors have found that, even when using the preferred methods of the known art, impurities are formed, e.g. the N-methylated species in which an amine hydrogen is replaced by a methyl group rather than by the methylenephosphonic acid moiety.